ANRIL upregulates TGFBR1 to promote idiopathic pulmonary fibrosis in TGF-β1-treated lung fibroblasts via sequestering let-7d-5p

Idiopathic pulmonary fibrosis (IPF) is a progressive and life-threatening respiratory disease characterized by worsening lung function due to excessive scarring. The objective of this study was to investigate the role of the long non-coding RNA ANRIL (antisense non-coding RNA in the INK4 locus) in the development of IPF. Our research revealed a significant increase in ANRIL expression in pulmonary fibrosis, consistent with prior studies indicating elevated ANRIL levels in fibrotic tissues. <i>In vitro</i> experiments demonstrated that elevated ANRIL expression promoted fibroblast activation, as evidenced by the upregulation of fibrosis-related markers. Mechanistically, we found that ANRIL interacts with let-7d-5p, a microRNA involved in gene regulation, acting as a sponge for let-7d-5p. Functional experiments confirmed a potential influence of let-7d-5p on fibroblast activation through direct interaction with ANRIL. Furthermore, our investigation identified TGFBR1 as a potential mediator of ANRIL’s fibrogenic effects. Silence of TGFBR1 mitigated the fibrotic phenotype induced by ANRIL overexpression. Collectively, these results suggest that ANRIL promotes fibroblast activation and fibrosis development, possibly through the let-7d-5p/TGFBR1 axis, indicating that ANRIL could be a potential therapeutic target for pulmonary fibrosis.

特发性肺纤维化（Idiopathic pulmonary fibrosis, IPF）是一种进行性、危及生命的呼吸系统疾病，其特征为过度瘢痕形成导致肺功能恶化。本研究旨在探究长链非编码RNA（long non-coding RNA）ANRIL（antisense non-coding RNA in the INK4 locus）在IPF发生发展中的作用。我们的研究发现，肺纤维化组织中ANRIL的表达显著升高，这与先前研究显示纤维化组织中ANRIL水平上调的结果一致。<i>In vitro</i>实验表明，ANRIL表达升高可促进成纤维细胞活化，纤维化相关标志物的上调为这一结果提供了证据。机制层面上，我们发现ANRIL与参与基因调控的微小RNA（microRNA）let-7d-5p相互作用，并充当其分子海绵。功能实验证实，let-7d-5p可通过与ANRIL的直接相互作用对成纤维细胞活化产生潜在影响。此外，我们的研究还发现TGFBR1是ANRIL促纤维化效应的潜在介导因子。沉默TGFBR1可减轻ANRIL过表达诱导的纤维化表型。综上，这些结果表明ANRIL可促进成纤维细胞活化及纤维化进展，其机制可能涉及let-7d-5p/TGFBR1轴，提示ANRIL有望成为肺纤维化治疗的潜在靶点。